Non-hodgkin s lymphomas are an important cause of cancer morbidity and mortality in the United States. The majority of these tumors arise in the B cell lineage and carry chromosome translocations involving the immunoglobulin loci. Expression of oncogenes in the vicinity of the breakpoint is deregulated, thereby contributing to cellular transformation. Lymphoid cells normally undergo somatic rearrangement of V, D, and J gene segments of antigen receptor loci, and there is evidence that this tissue-specific oncogenic mechanism represents aberrant V(D)J recombination. We have observed that mice with a combination of the scid mutation and targeted inactivation of the DNA-damage checkpoint gene p53 uniformly develop high-grade B cell lymphomas at 6-13 weeks of age. The majority of these tumors carry a t(12;15) which appears to involve the IgH locus on chromosome 12. Mutation of Rag-2 suppresses t(12;15) lymphomas in scid p53-/- mice, demonstrating that initiation of V(D)J recombination is a required element in the oncogenic pathway. Thus, we have identified for the first time a genetic pathway involving V(D)J recombinase, which leads reproducibly to a lymphoma-associated Ig locus translocation. The long-range goal of our investigation is to understand elements of the V(D)J recombination process which suppress the generation of chromosome translocations. Such tumor suppressors may be subverted in conditions which predispose to lymphoma development, such as inherited conditions, toxin exposure, infections, including EBV, and immunodeficiencies. We propose to clone translocation breakpoints, identify putative oncogenes and study why some oncogene loci are susceptible as translocation targets. Factors regulating the efficiency of aberrant V(D)J recombination, such as mutations in recombinase compnents or in genes mediating cellular responses to DNA damage are studied, and the mechanism of p53-mediated tumor suppression is investigated. By understanding the mechanisms which act to prevent translocations during lymphocyte gene rearrangement, we hope to develop models for testing the mechanism of lymphomagenic agents, including studies of how immune responses may contribute to tumor development. Ultimately, strategies to prevent lymphoma development in groups at increased risk may emerge.